Solving rare disease mysteries

Dr Elena Tucker, geneticist, Murdoch Childrens Research Institute, Melbourne

Dr Elena Tucker (credit: L’Oréal Australia)
Dr Elena Tucker (credit: L’Oréal Australia)

Dr Elena Tucker has brought peace of mind to families affected by rare energy disorders. She’s found genes responsible for some of these diseases.

Now, with the support of her 2014 L’Oréal For Women in Science Fellowship, she will look at hundreds of individual genomes to determine the causes of sex-determination disorders.

For the thousands of families affected by these rare disorders Elena’s work provides an understanding of the causes and opens a path to management and to potential treatments one day. And the techniques she’s developing underpin the broader development of personalised medicine.

For her PhD, Elena used high-throughput DNA sequencing to investigate the genetics of mitochondrial disease. Mitochondria are the membranous structures in the cell where food is converted into the energy that powers our bodies. Anything that disables them, such as the mutation of a gene, robs the body of the energy it needs to function. This can lead to symptoms such as seizures, muscle weakness, developmental delays, liver dysfunction, heart failure or blindness.

Elena discovered four genes, and helped in finding an additional four, within which mutations have a direct link to such conditions. This has accounted for a significant proportion of new genetic diagnoses of mitochondrial disease.

But her work has a much broader impact than that. She is one of the pioneers of personalised medicine, which is starting to link individual genomes to disease and potential treatment. In her research, she has been developing many of the techniques that pick out the gene sequences that cause disease, while the equipment and technology on which she depends is still developing rapidly around her.

That’s why her work has been published in high impact journals such as Nature Genetics, Science Translational Medicine, and Cell Metabolism.

To Elena, however, it is more significant that what she does is of practical medical use—that there is a direct line to the clinic. “It is important to me that there is concrete value to my research, giving parents answers, for instance, as to why their child is sick.”

Now Elena, who is a National Health and Medical Research Council (NHMRC) Peter Doherty Research Fellow at the Murdoch Childrens Research Institute (MCRI) and Honorary Fellow of The University of Melbourne’s Department of Paediatrics, is moving on to a different but equally important area of disease.

From the start of next year, she will use her genomic approaches to investigate disorders of sex development—the genetic conditions that lead to ambiguous genitalia, genital anomalies or gender characteristics that do not match the genetic sex. And the $25,000 she will receive as one of this year’s L’Oréal Australia and New Zealand For Women in Science Fellows will help launch her new work.

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Mitochondria began their existence as primitive bacteria. Later they became trapped in cells, but still retained some of their own genetic material. If these genes mutate or malfunction, the results can be devastating, particularly in children. There are also more than 1000 genes in the nucleus that encode proteins believed to have a role in mitochondrial function, many of which can cause mitochondrial disease when mutated.

Because genetic therapy is still in its infancy, it is rare that such genetically based diseases can be treated. But, says Elena, knowing there is a genetic cause of a condition is still advantageous. It brings not only peace of mind but sometimes also a capacity to manage the disease. An understanding of the cause can be the basis of genetic counselling for parents and may allow them to halt further expensive and sometimes painful tests. Most importantly, though, such knowledge is the first step on the research trail that can lead to therapy and cures.

When Elena began her mitochondrial work supervised by human geneticist Prof David Thorburn at MCRI in 2008, she gathered DNA from more than 100 patients with mitochondrial disease. Initially, 100 genes from each of these samples were sequenced at the Broad Institute of Harvard University and MIT in Boston, and the data were knocked into shape by the bioinformaticians there. Elena spent a month in Boston with Prof Vamsi Mootha and Dr Sarah Calvo, familiarising herself with the institute’s work and the kinds of analytical techniques she could use to sift through the data. She then came back to Australia to complete the project.

The sugars, fats and proteins that are broken down for energy in the mitochondria pass through a series of protein complexes that act as enzymes, controlling the process. The initial 100 genes that Elena sequenced were predicted to have a role in the assembly or function of Complex I. It was among the variants of these genes that she found two of the new genes for mitochondrial disease. This work highlighted the promise of high-throughput sequencing for genetic diagnosis.

By the time this part of work was completed, the technology had moved on to such a degree that she was able to sequence more than 1000 genes from another 44 patients with severe mitochondrial disease. This time all genes believed to encode mitochondrial proteins were selected, and another five new disease genes emerged.

Elena used a clever means of proving these really were causative disease genes. She took samples of common connective tissue cells from patients in which these genes were faulty, and grew them up in tissue culture. Then she infected the cells with carefully fashioned viruses containing good copies of the genes. If the virus corrected the fault and the mitochondria in the cultured cells began to function normally, Elena knew she had her quarry. And she could gather further evidence by asking the medical fraternity to supply her with more examples of people with mutations in these particular disease genes.

She proposes to apply much the same approach—sequencing and data analysis, followed by experimental proof—to her work on sex-development disorders. But things have moved on again. Not only has the equipment become more efficient and widespread, enough so that the initial sequencing can now be done at MCRI, but also there are software packages and local bioinformaticians who can help with the analysis.

Isolating new disease genes will be somewhat more difficult, however. Because the disorders on which she will be working are ‘developmental’, the genes involved are active during development and will not necessarily be active in the patients whose DNA sequences Elena will analyse. That means she cannot use the same tissue culture method as a means of proof. More likely she will be testing her outcomes in mice, a process likely to be more complex and take longer.

There are further complications. DNA sequencing brings with it several ethical dilemmas with which our society is only beginning to come to grips. Genetic analysis sometimes provides unwelcome information on paternity and on other serious genetic conditions which may carry both health and insurance implications. Also, not everyone—and particularly some members of the intersex community—assumes that such developmental anomalies are uniformly bad. That is why Elena will be working closely with medical geneticists and genetic counsellors.

“Winning the L’Oréal Fellowship is particularly important to me because I’ve had a break in my career,” says Elena, who will be returning to research after maternity leave and a bout of ill health. “It is important for me to be recognised still and, once back, it will allow me to hit the ground running.”


2011 PhD (medical genomics), The University of Melbourne/Murdoch Childrens Research Institute, Melbourne
2006 Bachelor of Science (Honours) (genetics), The University of Melbourne/St Vincent’s Institute, Melbourne

 Career highlights, awards, fellowships, grants

2013–present Postdoctoral Research Fellow, Investigating the molecular basis of disorders of sex development. Peter Doherty – Australian Biomedical Fellowship, Murdoch Childrens Research Institute
2013 Invited presentation, Victorian Institute of Forensic Medicine Seminar, Melbourne
2012 Commended for work into mitochondrial disease, Premier’s Commendation for Health and Medical Research
2012 Victorian Young Tall Poppy Science Award, Australian Institute of Policy and Science
2012 Invited presentation, AussieMit Conference, Melbourne
2012 Invited presentation, Gordon Research Conference, Boston, USA
2011–2012 Postdoctoral Research Fellow, Investigating the molecular basis of mitochondrial disease, Murdoch Childrens Research Institute
2011 Invited presentation, Institute of Neurology Besta, Italy
2011 New Investigator Award, Human Genetic Society of Australasia
2011 Kirby Travel Award, Human Genetic Society of Australasia
2009 One month collaborative residency, Broad Institute of Harvard and MIT, Boston, USA
2008 David Danks Scholarship, Murdoch Childrens Research Institute
2007 Research Assistant, Investigating the molecular basis of Parkinson’s disease, Howard Florey Institute

Top five publications

Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawform G, Burtt NP, Rivas M, Guiducci C, Bruno DL, Goldberger OA, Redman MC, Wiltshire E, Wilson CJ, Altshuler D, Gabriel SB, Daly MJ, Thorburn DR, Mootha VK (2010) High-throughput, pooled sequencing of a patient cohort reveals mutations in NUBPL and FOXRED1 that cause human complex I deficiency, Nature Genetics 42(10): 851–858. (Impact factor 35.209, 146 citations)

Tucker EJ, Hershman SG, Köhrer C, Belcher-Timme CA, Patel J, Goldberger OA, Christodoulou J, Silberstein JM, McKenzie M, Ryan MT, Compton AG, Jaffe JD, Carr SA, Calvo SE, RajBhandary UL, Thorburn DR and Mootha VK (2011) Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation, Cell Metabolism 14(3): 428–434. (Impact factor 17.551, 29 citations)

Tucker EJ, Wanschers BF, Szklarczyk R, Mountford HS, Wijeyeratne XW, van den Brand MA, Leenders AM, Rodenburg RJ, Reljić B, Compton AG, Frazier AE, Bruno DL, Christodoulou J, Endo H, Ryan MT, Nijtmans LG, Huynen MA and Thorburn DR (2013) Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression, PLOS Genetics 9(12): e1004034. (Impact factor 9.44, 0 citations)

Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, DiMauro S, Thorburn DR and Mootha VK (2012) Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing, Science Translational Medicine 4(118): 118ra10. (Impact factor 10.757, 99 citations)

Tucker EJ, Mimaki M, Compton AG, McKenzie M, Ryan MT and Thorburn DT (2011) Next Generation Sequencing in molecular diagnosis: NUBPL mutations highlight the challenges of variant detection and interpretation, Human Mutation 33(2):411–418. (Impact factor 5.213, 19 citations)

Dr Elena Tucker (credit: L’Oréal Australia)
Dr Elena Tucker (credit: L’Oréal Australia)
Dr Elena Tucker (credit: L’Oréal Australia)
Dr Elena Tucker (credit: L’Oréal Australia)
Dr Elena Tucker (credit: L’Oréal Australia)
Dr Elena Tucker (credit: L’Oréal Australia)
Dr Elena Tucker (credit: L’Oréal Australia)